Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma

M. B. Meads, B. Fang, L. Mathews, J. Gemmer, L. Nong, I. Rosado-Lopez, T. Nguyen, J. E. Ring, W. Matsui, A. R. MacLeod, J. A. Pachter, L. A. Hazlehurst, J. M. Koomen, K. H. Shain

Research output: Contribution to journalArticle

Abstract

Multiple myeloma (MM) remains an incurable malignancy due, in part, to the influence of the bone marrow microenvironment on survival and drug response. Identification of microenvironment-specific survival signaling determinants is critical for the rational design of therapy and elimination of MM. Previously, we have shown that collaborative signaling between β 1 integrin-mediated adhesion to fibronectin and interleukin-6 confers a more malignant phenotype via amplification of signal transducer and activator of transcription 3 (STAT3) activation. Further characterization of the events modulated under these conditions with quantitative phosphotyrosine profiling identified 193 differentially phosphorylated peptides. Seventy-seven phosphorylations were upregulated upon adhesion, including PYK2/FAK2, Paxillin, CASL and p130CAS consistent with focal adhesion (FA) formation. We hypothesized that the collaborative signaling between β 1 integrin and gp130 (IL-6 β receptor, IL-6 signal transducer) was mediated by FA formation and proline-rich tyrosine kinase 2 (PYK2) activity. Both pharmacological and molecular targeting of PYK2 attenuated the amplification of STAT3 phosphorylation under co-stimulatory conditions. Co-culture of MM cells with patient bone marrow stromal cells (BMSC) showed similar β 1 integrin-specific enhancement of PYK2 and STAT3 signaling. Molecular and pharmacological targeting of PYK2 specifically induced cell death and reduced clonogenic growth in BMSC-adherent myeloma cell lines, aldehyde dehydrogenase-positive MM cancer stem cells and patient specimens. Finally, PYK2 inhibition similarly attenuated MM progression in vivo. These data identify a novel PYK2-mediated survival pathway in MM cells and MM cancer stem cells within the context of microenvironmental cues, providing preclinical support for the use of the clinical stage FAK/PYK2 inhibitors for treatment of MM, especially in a minimal residual disease setting.

Original languageEnglish (US)
Pages (from-to)2723-2734
Number of pages12
JournalOncogene
Volume35
Issue number21
DOIs
StatePublished - May 1 2016

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Focal Adhesion Kinase 2
Multiple Myeloma
Cell Death
STAT3 Transcription Factor
Integrins
Focal Adhesions
Neoplastic Stem Cells
Mesenchymal Stromal Cells
Survival
Interleukin-6
Phosphorylation
Pharmacology
Paxillin
Interleukin-6 Receptors
Aldehyde Dehydrogenase
Phosphotyrosine
Residual Neoplasm
Coculture Techniques
Transducers
Fibronectins

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Meads, M. B., Fang, B., Mathews, L., Gemmer, J., Nong, L., Rosado-Lopez, I., ... Shain, K. H. (2016). Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. Oncogene, 35(21), 2723-2734. https://doi.org/10.1038/onc.2015.334

Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. / Meads, M. B.; Fang, B.; Mathews, L.; Gemmer, J.; Nong, L.; Rosado-Lopez, I.; Nguyen, T.; Ring, J. E.; Matsui, W.; MacLeod, A. R.; Pachter, J. A.; Hazlehurst, L. A.; Koomen, J. M.; Shain, K. H.

In: Oncogene, Vol. 35, No. 21, 01.05.2016, p. 2723-2734.

Research output: Contribution to journalArticle

Meads, MB, Fang, B, Mathews, L, Gemmer, J, Nong, L, Rosado-Lopez, I, Nguyen, T, Ring, JE, Matsui, W, MacLeod, AR, Pachter, JA, Hazlehurst, LA, Koomen, JM & Shain, KH 2016, 'Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma', Oncogene, vol. 35, no. 21, pp. 2723-2734. https://doi.org/10.1038/onc.2015.334
Meads MB, Fang B, Mathews L, Gemmer J, Nong L, Rosado-Lopez I et al. Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. Oncogene. 2016 May 1;35(21):2723-2734. https://doi.org/10.1038/onc.2015.334
Meads, M. B. ; Fang, B. ; Mathews, L. ; Gemmer, J. ; Nong, L. ; Rosado-Lopez, I. ; Nguyen, T. ; Ring, J. E. ; Matsui, W. ; MacLeod, A. R. ; Pachter, J. A. ; Hazlehurst, L. A. ; Koomen, J. M. ; Shain, K. H. / Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. In: Oncogene. 2016 ; Vol. 35, No. 21. pp. 2723-2734.
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